Use of tetrahydrocortisol to prevent elevations in intraocular pressure caused by corticosteroids

ABSTRACT

Pharmaceutical compositions useful in the treatment of ophthalmic inflammation and methods of treating ophthalmic inflammation with those compositions are disclosed. The compositions contain a combination of a glucocorticoid and tetrahydrocortisol. The tetrahydrocortisol serves to substantially prevent any significant increases in intraocular pressure which might otherwise be experienced by the patient as a side effect of the glucocorticoid component of the compositions. The therapeutic interaction of the two components therefore allows the potent antiinflammatory properties of the glucocorticoids to be utilized without fear of elevating intraocular pressure. A method of preventing increases in intraocular pressure attributable to systemic or topical corticosteroid therapy is also disclosed. That method involves the administration of a pharmaceutical composition containing tetrahydrocortisol to a patient receiving such therapy.

This is a continuation of application Ser. No. 07/399,349, filed Aug.28, 1989 now abandoned, which is a continuation of Ser. No. 07/139,227,filed Dec. 29, 1987 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to the field of ophthalmology. Moreparticularly, this invention relates to the treatment of inflamed oculartissue.

Many compounds classified as glucocorticoids, such as dexamethasone andprednisolone, are very effective in the treatment of inflamed tissues,but in certain patients, these compounds cause elevations in intraocularpressure. Patients who experience elevations in intraocular pressurewhen treated with glucocorticoids are generally referred to as "steroidresponders". The elevations in intraocular pressure are of particularconcern in patients who are already suffering from elevated intraocularpressures, such as glaucoma patients. Moreover, there is always a riskthat the use of glucocorticoids in patients who have normal intraocularpressures will cause elevations in pressure that result in damage toocular tissue. Since therapy with glucocorticoids is frequently longterm (i.e., several days or more), there is potential for significantdamage to ocular tissue as a result of prolonged elevations inintraocular pressure attributable to that therapy.

The following articles may be referred to for further backgroundinformation concerning the well recognized association betweenophthalmic glucocorticoid therapy and elevations in intraocularpressure: Kitazawa, "Increased Intraocular Pressure Induced byCorticosteroids", American Journal of Ophthalmology, Vol. 82, pages492-495 (1976); Cantrill et al., "Comparison of In Vitro Potentcy ofCorticosteroids with Ability to Raise Intraocular Pressure", AmericanJournal of Ophthalmology, Vol. 79, pages 1012-1016 (1975); and Mindel etal., "Comparative Ocular Pressure Elevation by Medrysone,Fluorometholone, and Dexamethasone Phosphate", Archives ofOphthalmology, Vol. 98, pages 1577-1578 (1980).

One approach to solving the foregoing problems has been to search forcompounds which are capable of alleviating ophthalmic inflammationwithout elevating intraocular pressure. The inventions described in U.S.Pat. No. 4,686,214 and in copending U.S. patent application Ser. No.864,610, filed May 19, 1986, represent two examples of this approach.Notwithstanding the success of the therapies described in theabove-cited patent and patent application, there continues to be a needfor still further improvements in the treatment of ophthalmicinflammation, such as an improvement which would allow potentglucocorticoids to be utilized to treat inflamed ocular tissue withoutfear of elevating intraocular pressure.

SUMMARY OF THE INVENTION

A principal objective of the present invention is the provision of atherapy for ophthalmic inflammation which allows the potentantiinflammatory activity of the glucocorticoids to be employed withoutfear of elevating intraocular pressure. A further objective of theinvention is the provision of methods of treatment and ophthalmiccompositions useful in that therapy.

Another objective of the present invention is the provision of aprophylactic method of treatment wherein the elevations in intraocularpressure sometimes associated with corticosteroid therapy aresubstantially prevented.

The foregoing objectives and other general objectives of the presentinvention are met by the provision of a therapy for ophthalmicinflammation wherein the elevations in intraocular pressure caused byglucocorticoids are substantially prevented. The therapy involves thecombination of a glucocorticoid with a second compound which prevents orantagonizes the intraocular pressure elevating effect of theglucocorticoid. The second compound is tetrahydrocortisol. It has beendiscovered that the intraocular pressure ("IOP") elevating effect ofglucocorticoids can be eliminated without adversely affecting theantiinflammatory activity of the glucocorticoids. Thus, the therapy ofthe present invention makes it possible to employ the potent topicalantiinflammatory properties of the glucocorticoids without causing anysignificant elevations in intraocular pressure.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention is based on the combination of one or more potentglucocorticoids with tetrahydrocortisol. It has been discovered thattetrahydrocortisol antagonizes the IOP elevating effect ofglucocorticoids. It was previously discovered that tetrahydrocortisol iseffective in controlling intraocular pressure; that discovery is thesubject of U.S. patent application Ser. No. 864,610, filed May 19, 1986,the entire contents of which are hereby incorporated in the presentspecification by reference. The intraocular hypotensive effect oftetrahydrocortisol is reported by A. Louis Southren et al. inInvestigative Ophthalmology & Visual Science, Vol. 28, pages 901-903(May 1987); the entire contents of that report are also incorporatedherein by reference.

It has been postulated that tetrahydrocortisol controls intraocularpressure by antagonizing the action of 5-alpha and/or5-beta-dihydrocortisol, which are two substances that are believed toplay a significant role in a metabolic imbalance involving thetrabecular meshwork cells of the eye and, ultimately, elevations inintraocular pressure. The present invention is based on the finding thattetrahydrocortisol somehow antagonizes the IOP elevating effect ofglucocorticoids. The mechanism by which tetrahydrocortisol prevents orantagonizes the IOP elevating effect of glucocorticoids is not totallyunderstood at this point. While applicants do not wish to be bound byany theory, one possible explanation is that tetrahydrocortisolinterferes with the action of glucocorticoids on trabecular meshworkcells, thereby blocking or reversing the IOP elevating effect of theglucocorticoids.

Tetrahydrocortisol is a known compound. It has a molecular weight of366.5, and an empirical formula of C₂₁ H₃₄ O₅. The compound iscommercially available and may, for example, be obtained from ResearchPlus, Inc., Post Office Box 324, Bayonne, N.J., or Steraloids, Inc.,P.O. Box 310, Wilton, N.H. 03086. It may also be synthesized if desired.The general approach to synthesis involves treating tetrahydrocortisolacetate with semicarbazide to form 20-semi-carbazone. This is dissolvedin solution and reduced with potassium borohydride. It is then suspendedin methylene chloride and treated with hydrochloric acid. The product isstable at room temperature and requires no extraordinary storageprecautions. Tetrahydrocortisol has the following formula: ##STR1##

Tetrahydrocortisol may exist in several stereoisomeric forms.Specifically, with regard to stereoisometry, for tetrahydrocortisol itrefers to relative positions of the hydroxyl and hydrogen groups at the3,5 positions, as to whether or not they are above or below the plane ofthe ring structure. Alpha position refers to below the plane of the ringstructure, and beta refers to above the ring structure. Thus,tetrahydrocortisol may exist as 3-alpha, 5-beta; 3-alpha, 5alpha;3-beta, 5-alpha; and 3-beta, 5-beta. The preferred isomer for use inthis invention is 3-alpha, 5-beta-tetrahydrocortisol. The ringcontaining the 1-5 positions is referred to as the "A-ring."

The glucocorticoids which may be employed in the present inventioninclude all pharmaceutically acceptable compounds which are effective inthe treatment of inflamed ocular tissue. The preferred glucocorticoidsinclude dexamethasone, fluorometholone, medrysone, betamethasone,triamcinolone, prednisone, prednisolone, hydrocortisone, andpharmaceutically acceptable salts thereof. Further examples ofglucocorticoids include prednicarbate; deflazacort; halomethasone;tixocortol; prednylidene (21-diethylaminoacetate); prednival;paramethasone; methylprednisolone; meprednisone; maztpredone;isoflupredone; halopredone acetate; halcinonide; formocortal;flurandrenolide; fluprednisolone; flurprednidine acetate; fluperoloneacetate; fluocortolone; fluocortin butyl; fluocinonide; fluocinoloneacetonide; flunisolide; flumethasone; fludrocortisone; fluclorinide;enoxolone; difluprednate; diflucortolone; diflorasone diacetate;desoximetasone (desoxymethasone); desonide; descinolone; cortivazol;corticosterone; cortisone; cloprednol; clocortolone; clobetasone;clobetasol; chloroprednisone; cafestol; budesonide; beclomethasone;amcinonide; allopregnane acetonide; alclometasone;21-acetoxypregnenolone; tralonide; diflorasone acetate;deacylcortivazol; RU-26988; budesonide; and deacylcortivazol oxetanone.All of the above-cited glucocorticoids are known compounds. Furtherinformation about the compounds may be found, for example, in The MerckIndex, Tenth Edition (1983), and the publications cited therein, theentire contents of which are hereby incorporated in the presentspecification by reference.

In accordance with the invention, topical ophthalmic compositionscontaining one or more glucocorticoids and a second component comprisingtetrahydrocortisol are provided. The compositions will contain the oneor more glucocorticoids in an antiinflammatory effective amount and willcontain an amount of tetrahydrocortisol effective to inhibit the IOPelevating effect of the glucocorticoids. The amount of each componentwill depend on various factors, such as the relative tendency of certainglucocorticoids to cause IOP elevations, the severity and type of ocularinflammation being treated, the estimated duration of the treatment, andso on. In general, the ratio of the amount of glucocorticoid totetrahydrocortisol will be in the range of 10:1 to 1:20. Theconcentration of the glucocorticoid component will typically be in therange of from about 0.01% to about 2.0% by weight. The concentration oftetrahydrocortisol will typically be in the range of from about 0.05% toabout 5.0% by weight.

The above-described active ingredients may be incorporated into varioustypes of ophthalmic formulations for delivery to the eye. For example,the active ingredients may be combined with ophthalmologicallyacceptable preservatives, surfactants, viscosity enhancers, buffers,toxicity agents and water to form an aqueous, sterile ophthalmicsuspension. In order to prepare sterile ophthalmic ointmentformulations, the active ingredients are combined with a preservative inan appropriate vehicle, such as mineral oil, liquid lanolin, or whitepetrolatum. Sterile ophthalmic gel formulations may be prepared bysuspending the active ingredient in a hydrophilic base prepared from thecombination of Carbopol-940 (a carboxy vinyl polymer available from theB. F. Goodrich Company) according to published formulations foranalogous ophthalmic preparations; preservatives and tonicity agents canbe incorporated. The specific type of formulation selected will dependon various factors, such as the severity and type of ophthalmicinflammation being treated, and dosage frequency. Ophthalmic solutions,suspensions, ointments and gels are the preferred dosage forms.

The following Example is presented to further illustrate thecompositions of the present invention.

EXAMPLE

The following formulation is representative of the compositions of thepresent invention.

    ______________________________________                                        Ingredient       Amount (wt. %)                                               ______________________________________                                        THF              1.0                                                          Dexamethasone    0.1                                                          Tyloxapol        0.01 to 0.05                                                 HPMC             0.5                                                          Benzalkonium chloride                                                                           0.01                                                        Sodium chloride  0.8                                                          Edetate Disodium  0.01                                                        NaOH/HCl         q.s. pH 7.4.sup.                                             Purified water   q.s. 100 mL                                                  ______________________________________                                    

The formulation is prepared by first placing a portion of the purifiedwater into a beaker and heating to 90° C. Thehydroxypropylmethylcellulose (HPMC) is then added to the heated waterand mixed by means of vigorous vortex stirring until all of the HPMC isdispersed. The resulting mixture is then allowed to cool whileundergoing mixing in order to hydrate the HPMC. The resulting solutionis then sterilized by means of autoclaving in a vessel having a liquidinlet and a hydrophobic, sterile air vent filter.

The sodium chloride and the edetate disodium are then added to a secondportion of the purified water and dissolved. The benzalkonium chlorideis then added to the solution, and the pH of the solution is adjusted to7.4 with 0.1M NaOH/HCl. The solution is then sterilized by means offiltration.

The tetrahydrocortisol (THF) and dexamethasone are sterilized by eitherdry heat or ethylene oxide. If ethylene oxide sterilization is selected,aeration for at least 72 hours at 50° C. is necessary. The sterilizedTHF and dexamethasone are weighed aseptically and placed into apressurized ballmill container. The tyloxapol, in sterilized aqueoussolution form, is then added to the ballmill container. Sterilized glassballs are then added to the container and the contents of the containerare milled aseptically at 225 rpm for 16 hours, or until all particlesare in the range of approximately 5 microns.

Under aseptic conditions, the micronized drug suspension formed by meansof the preceding step is then poured into the HPMC solution with mixing.The ballmill container and balls contained therein are then rinsed witha portion of the solution containing the sodium chloride, the edetatedisodium and benzalkonium chloride. The rinse is then added asepticallyto the HPMC solution. The final volume of the solution is then adjustedwith purified water and, if necessary, the pH of the solution isadjusted to pH 7.4 with NaOH/HCl.

The treatment method of the present invention comprises application ofan effective amount of the above-described compositions to the eye. Thedosage regimen utilized will depend on the severity and type ofinflammation being treated, as well as various clinical factors, suchas, the patient's age, sex, weight and medical history. In general, theabove-described compositions may be topically applied, for example, asdrops to the upper globe, or as a 0.5-1 cm strip of ointment or gel tothe lower conjunctival sac of the eye. Suspensions will generally beapplied 1 to 4 times daily, while ointments or gels will generally beapplied once or twice daily. The application of sustained releaseformulations (e.g., polymer based gels) once daily at bedtime will bepreferred in some conditions.

The present invention primarily concerns a new and useful therapeuticapproach to treating ophthalmic inflammation. A different, but relatedaspect of the present invention involves the use of tetrahydrocortisolin connection with the systemic use of corticosteroids. Morespecifically, the present invention is also directed to the provision ofa method of preventing elevations of intraocular pressure in patientsreceiving corticosteroids systemically or topically at a site other thanthe eye. This other aspect of the invention might therefore be describedas a prophylactic therapy designed to protect patients from anophthalmic side effect of systemic and topical corticosteroid therapy.The therapy comprises the administration of a pharmaceutical compositioncontaining a therapeutically effective amount of tetrahydrocortisol. Inthis instance, the phrase "therapeutically effective amount" means anamount which is sufficient to substantially prevent or reverse anyincreases in intraocular pressure attributable to the corticosteroidtherapy. The dosage regimen utilized will depend on the nature of thecorticosteroid therapy and the general predisposition of the patient toelevations in intraocular pressure, as well as various other factorssuch as the patients age, sex, weight and medical history. The therapywill generally comprise topical administration of compositions which areessentially the same as those described above, except for the absence ofa glucocorticoid.

What is claimed is:
 1. In a method of treating ocular inflammation in ahuman patient by topically applying to an eye of the patient a topicalophthalmic composition containing an antiinflammatory effective amountof a glucocorticoid and a pharmaceutically acceptable carrier therefor,the improvement which comprises including in said composition an amountof tetrahydrocortisol effective to control elevations of intraocularpressure caused by the glucocorticoid, whereby the topical applicationof the glucocorticoid to the eye does not significantly increase theintraocular pressure of the eye.
 2. A method according to claim 1,wherein the glucocorticoid is selected from the group consisting ofdexamethasone, fluorometholone, medrysone, betamethasone, triamcinolone,prednisone, prednisolone, hydrocortisone, and pharmaceuticallyacceptable salts thereof.
 3. A method according to claim 1, wherein theratio of the amount of glucocorticoid to the amount oftetrahydrocortisol is in the range of 10:1 to 1:20.
 4. A methodaccording to claim 1, wherein the glucocorticoid is contained in thecomposition in an amount of from about 0.01% to about 2.0% by weight. 5.A method according to claim 1, wherein tetrahydrocortisol is containedin the composition in an amount of from about 0.05% to about 5.0% byweight.
 6. A method according to claim 1, wherein the patient is asteroid responder.
 7. A method of treating ophthalmic inflammation in ahuman patient which comprises topically applying to an eye of thepatient a therapeutically effective amount of a pharmaceuticalcomposition comprising an antiinflammatory effective amount of aglucocorticoid and an amount of tetrahydrocortisol effective to controlelevations of the intraocular pressure of the patient caused by theglucocorticoid, whereby the risk of elevating the intraocular pressureof the patient as a result of application of the glucocorticoid issubstantially eliminated.
 8. A method according to claim 7, wherein theglucocorticoid is selected from dexamethasone, fluorometholone,medrysone, betamethasone, triamcinolone, prednisone, prednisolone,hydrocortisone, and pharmaceutically acceptable salts thereof.
 9. Amethod according to claim 7, wherein the ratio of the amount ofglucocorticoid to the amount of tetrahydrocortisol is in the range of10:1 to 1:20.
 10. A method according to claim 7, wherein theglucocorticoid is contained in the composition in an amount of fromabout 0.01% to about 2.0% by weight.
 11. A method according to claim 7,wherein tetrahydrocortisol is contained in the composition in an amountof from about 0.05% to about 5.0% by weight.
 12. A method according toclaim 7, wherein the patient is a steroid responder.